TWI327910B - - Google Patents

Description

1327910 (1) Technical Field of the Invention The present invention relates to a pharmaceutical preparation which is selected from the above-mentioned arginine amide amines, salts thereof, and a substance in which such hydrates are in an active ingredient. . [Prior Art] selected from the following general formula (I)

HN H2N CH2-CH2-CH2-CH-COR1 ...(I)

(In the above general formula (I), R1 represents (2R, 4R)-4-homo--2-carboxypiperidinyl, and R2 represents a phenyl group or a condensed polycyclic compound residue as defined below, R2 may a substituent having one or more amine groups selected from a lower alkyl group, a lower alkoxy group or a lower alkyl group. The condensed polycyclic compound residue represents a condensed polycyclic compound residue containing a benzene ring, The benzene ring is bonded to the sulfur atom of the sulfonyl group in the above general formula (I), and the other ring of the condensed hetero ring on the benzene ring may be the same, and the total number of carbon atoms of the ring constituting the residue of the polycyclic compound is The above-mentioned arginine amide amines, the salts thereof, and the hydrates of the above-mentioned hydrates are compounds having antithrombin activity (Specially Opened 5-6 - 15) Japanese Laid-Open Patent Publication No. Hei. No. 5, No. 5, No. 5, 5, 3, 499, and Japanese Patent Laid-Open Publication No. Hei 59-9221-3. Among them argatroban((2R:4R)-l-[N2-((RS)-3·methyl -1 .2.3.4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid hydrate ) 7 - (2) 1327910 (211,411)-1-[>^2-(()^)-3_methyl-1; 2,3,4-tetrahydro-8-quino-L - Spermine sulfhydryl]-4-methyl-2-piperidinecarboxylic acid hydrate), general: The name Novastan (registered trademark, Mitsubishi Pharma shares, etc., commercially available pharmaceutical products. The above general formula (I) The arginine acid g argatroban (argatroban) is poorly soluble in water, and the preparations currently sold are prepared into a 20 mL acupuncture tube. 20 mL of his general injection is relatively large in volume, because the needle tube itself is an item. There is a need for a large space for the storage or disposal of the needle tube. In addition, because the speed of disappearance of the argatroban administered in the blood is required to be treated in the blood, it must be continuously administered, so it is necessary to prepare the droplets when administered. However, when using a commercially available agent, it is necessary to first draw the solution from the solution into the syringe to the syringe to prepare the drip. Because at this time, the 20 mm L large-volume agent is attracted by the needle tube. The liquid is supplied to the syringe, and it is required to operate the preparation which is required to provide convenience in advance. Although various high-concentration solutions of the guanamine or argatroban represented by the above general formula (I) are tried, the preparations of the additives such as the active agent are As a safety of an injection (Japanese Patent Laid-Open No. 10- 3 1 6 5 9 5), or a complicated preparation requiring emulsification or the like (Japanese Patent Laid-Open Publication No. Hei No. Hei No. Hei. High-concentration ethanol represents a high-concentration method for preparing a high-concentration argatroban solution (specially), which is a commercial company. I amines or guanidines are also a large problem. The degree is fast, for the injection of blood vessels, the mixing of the needles between the tubes, so the arginine addition interface is not high manufacturing steps, it is not alcohol, etc. 1-31727 -8- (3) 1327910 Bulletin). Although the injection preparations marketed in the United States are needles, the argatroban is dissolved using a local concentration of ethanol. The use of high-concentration ethanol is due to the adverse effects of ethanol, such as the occurrence of a tensile or central action. When the additive is used, it is required to reduce the amount of ethanol as much as possible. DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION As described above, the above-described arginine amide is a medicinal preparation, which affects the convenience of a medical site. In addition, the 'medicine preparation which is excellent in preservation stability and which is safe for smoking is also a subject of the present invention. The results of the efforts of the inventors of the present invention, based on the provision of the package of 1 mg/mL or more, are about 〇mg/mL or less as an active ingredient, and the arginine amides, salts and hydrates thereof represented by the general formula (I). a solution of a group of substances, the solution is filled with a concentration of more than 1 mL of a container of about 20 mL or less, and the concentration of the drug is about 1 mg/mL or more, and is about 〇mg/rnL or less selected from the above general formula (ί) The substance represented by the group of arginine amides and the hydrates thereof, and the composition of the solution having a viscosity of about '5 mPa·s_1 or less at a shear rate is found to solve the above problem. The present invention has been completed. That is, the following pharmaceutical preparations are provided by the present invention. (]) includes a sputum containing a concentration of 1 mg/mL or more, about 2.5 ηι 1 2 5 0 m g for inhibiting vasodilation, as a therapeutic ingredient of the present invention, and manufacturing a simple concentration containing the selected from the above and the like For the capacity of the agent, or the active ingredient, the salt thereof, the drug formed by 35.8 s-1, 10 m g / m L (4) 1327910 as the active ingredient is selected from the following general formula (1) a solution of the arginine amide amine, a salt thereof, and a group of such hydrates (but the solution is a solution containing at least water). The solution is filled with a capacity of about 1 mL or more. a pharmaceutical preparation of the type of a container of about 20 mL or less

HN H2N CH2-CH2-CH2-CH-COR1 NH-S02

··· ( I

(In the above general formula (I), w represents (2R, 4R) - 4 - alkyl-2-carboxypiperidinyl, and R2 represents a phenyl group or a condensed polycyclic compound residue as defined below, R2 may a substituent having one or more amine groups selected from a lower alkyl group, a lower alkoxy group or a lower alkyl group. The condensed polycyclic compound residue represents a condensed polycyclic compound residue containing a benzene ring, The benzene ring is bonded to the sulfur atom of the sulfonyl group in the above general formula (I), and the other ring of the condensed heterocyclic ring on the benzene ring may constitute the total number of carbon atoms of the ring of the polycyclic compound residue. 7 to 14 residues)

(2) The pharmaceutical preparation according to the above (1), wherein R in the general formula (I) is (2R, 4R)-4-methyl-2-carboxylidine group, and R2 represents 3·methyl 3,4 - Tetrahydro-8-indole quinolyl. (3) The pharmaceutical preparation according to the above (1), which is a pharmaceutical preparation according to any one of the above (1) to (3), which is administered as an injection or used for preparation. Drops. (5) The pharmaceutical preparation according to any one of the above (1) to (4), wherein the container has a capacity of about 10 mL or less. (10) The pharmaceutical preparation according to any one of the above (1) to (4), wherein the container has a capacity of about 2 mL. (7) The pharmaceutical preparation according to any one of the above (1) to (6), which comprises a guanamine hydrochloride, a salt thereof, and a hydrate thereof, which are contained in an amount of about 5 m g/mL. a solution of the substance of the group. (8) The pharmaceutical preparation according to any one of the above (1) to (7), which comprises about 1 mg of a guanamine amide selected from the above, a salt thereof, and a hydrate thereof a solution of the substance. (9) The pharmaceutical preparation according to any one of the above (1) to (8), wherein the viscosity of the solution is about 15 mPa·s_1 or less at a shear rate of about 35.8 s-1 at 25 °C. (1) The pharmaceutical preparation according to any one of the above (1) to (8), wherein the viscosity of the solution is at about 5 5 ° C and a shear rate of about 7 1.6 s -1 , which is about 10 mPa·s_1 or less ( 11) The pharmaceutical preparation according to any one of the above (1) to (10), wherein the pH of the solution is from about 4 to about 7. (12) The pharmaceutical preparation according to any one of the above (1) to (1), wherein the p Η of the solution is from about 5 to about 7 » (13) according to any one of the above (1) to (2). The pharmaceutical preparation substantially inhibits the formation of substances other than the active ingredient after heat sterilization. (14) The pharmaceutical preparation according to any one of the above (1) to (12), which is sterilized by heating, and stored at 40 ° C for 6 months, and the production of substances other than the active ingredient is inhibited to be less than about 0.2%. . (15) The pharmaceutical product -11-(6) 1327910 according to any one of the above (1) to (14), wherein the container is a needle tube. (16) The pharmaceutical preparation according to any one of the above (1) to (15), wherein the solution contains a monohydric alcohol. (1) The pharmaceutical preparation according to (16) above, wherein the monohydric alcohol is ethanol. (1) The pharmaceutical preparation according to any one of the above (1), wherein the one alcohol content in the solution is about 25% (w/v) or less.

(1) The pharmaceutical preparation according to (1) above, wherein the solution contains about 20% (w/v) or less of ethanol. (20) The pharmaceutical preparation according to any one of the above (1) to (19), wherein the solution contains a polyhydric alcohol. (21) The pharmaceutical preparation according to (20) above, wherein the polyol is glycerin. (22) The pharmaceutical preparation according to (20) or (21) above, wherein the polyol content in the solution is about 30% (w/v) or more.

(23) The pharmaceutical preparation according to (20) or (21) above, wherein the content of the polyol in the solution is about 40% (w/v) or more. (24) The pharmaceutical preparation according to any one of the above (1) to (23), wherein the solution contains substantially no sugar. (2) The pharmaceutical preparation according to any one of the above (1) to (2), wherein the solution contains a saccharide. (26) The pharmaceutical preparation according to (25) above, wherein the saccharide is sorbitol. (27) Included in the presence of a concentration of 1 mg/mL or more, about 0 mg/mL or less as an active ingredient, selected from the following general formula (I), 精-12-(7) (7) 1327910 amine 'The salt, and the group of such hydrates, have a viscosity of about 5 5 ° C, a shear rate of about 35.8 s -1 , and a solution of about i5 mPa · s -1 or less (but the solution is at least A pharmaceutical composition containing a solution of water). HN^ Η h2n》—N_CWCH2-〒布COR1 ...(1) NH—SO, (In the above general formula (I), R1 represents (2R, 4R) - 4 — Institute base 2- 2 residue D base, R2 system Represents a phenyl group or a condensed polycyclic compound residue as defined below, and R2 may have one or more substituents selected from lower alkyl 'lower alkoxy groups or amine groups substituted with lower alkyl groups. The residue of the compound of the formula is a residue of a condensed polycyclic compound containing a benzene ring bonded to a sulfur atom of the above sulfonyl group in the general formula (I), and the condensed heterocyclic ring on the benzene ring may be other a ring having a total number of carbon atoms of 7 to 14 in the ring constituting the residue of the polycyclic compound) (2 8) The pharmaceutical composition described in the above (2 7), having a viscosity of about 25 ° C, At a shear rate of 71.6 s-1, it is about l〇mPa·s-1 or less. (29) The pharmaceutical composition according to the above (27) or (28), wherein R1 in the general formula (I) is (2R, 4R)-4-methyl-2-carboxypiperidinyl, and R2 is 3-methyl Base-1,2,3,4-tetrahydro-8-indole quinolyl. (30) The pharmaceutical composition according to any one of the above (27) to (29), wherein the arginine amide is an argatroban. (31) The pharmaceutical composition according to any one of the above (27) to (30), which is administered as an injection or used for modulating a drip. (3) The pharmaceutical composition-13-(8) 1327910 according to any one of the above (2-7) to (3), which comprises about 5 mg/mL of arginine amide selected from the above, A solution of a salt, and a group of such hydrates. (3) The pharmaceutical composition according to any one of the above-mentioned items (2-7) to (3), which comprises about 〇mg of the above-mentioned arginine amide amine salt, and the hydration thereof a solution of a group of substances. (34) The pharmaceutical composition according to any one of the above (27) to (33) wherein the pH of the solution is from about 4 to about 7. (3) The pharmaceutical composition according to any one of the above (2-7) to (3), wherein the pH of the solution is from about 5 to about 7. (36) The pharmaceutical composition according to any one of the above (27) to (35), which substantially inhibits the formation of a substance other than the active ingredient after heat sterilization. (37) The pharmaceutical composition according to any one of the above (27) to (36), which is heat-sterilized and stored at 4 ° C for 6 months, and the production of substances other than the active ingredient is inhibited by about 〇 . 2 % or less. (38) The pharmaceutical composition according to any one of the above (27) to (37), wherein the solution contains a monohydric alcohol. (39) The pharmaceutical preparation according to the above (3), wherein the alcohol is ethanol (40), or the pharmaceutical composition solution according to any one of (39) is about 25 % ( w/v) or less. The solution contains about (41) the pharmaceutical preparation described in the above (40), and 20% (w/v) or less of ethanol. (4 2 ) Any of the above (2 7 ) to (4 1 ) The pharmaceutical composition of the above-mentioned (42), wherein the polyol is glycerin, is contained in the pharmaceutical composition of the above-mentioned (42). (44) The pharmaceutical composition according to (42) or (43) above, wherein the polyol in the solution is about 30% (W/V) or more. (45) The pharmaceutical composition according to (42) or (43) above, wherein the polyol in the solution is about 40% (w/V) or more. (46) The pharmaceutical composition according to any one of the above (27) to (G), wherein the solution does not contain a saccharide. (47) The pharmaceutical composition according to any one of the above (27) to (45), wherein the solution contains a saccharide. (48) The pharmaceutical composition 'The saccharide' described in the above (4<7) is sorbitol. (49) A medicine comprising about 1 mg/mL or more, about 10 mg/mL or less of argatroban as an active ingredient, a viscosity of 25 ° C, a shear rate of about 35.8 s 1 , and a solution of about 15 mPa · s _ 1 or less Composition. (50) argatroban containing about 1 mg/mL or more and about 10 mg/mL or less, after heat sterilization, the preparation of substances other than the active ingredient after storage at 4 ° C for 6 months, respectively inhibiting the solution to about 0.2% or less The resulting pharmaceutical composition. (51) Argatroban containing about 1 mg/mL or more and about 0 mg/mL or less, and after heat sterilization, the production of substances other than the active ingredient after storage at 40 ° C for 6 months is suppressed to about 0.2% or less, respectively. The viscosity is 25 ° C, a shearing speed of about 71.6 s -1, a pharmaceutical composition formed by a solution of about 10 mPa·s -1 or less. 15- (10) (10) 1327910 (52) Containing about 5 mg/mL or less of argatroban, after heat sterilization, the formation of substances other than the active ingredient after storage at 40 ° C for 6 months is inhibited by about 0.2%. Hereinafter, the viscosity is about 25 ° C, at a shear rate of about 7 1 .6, about a pharmaceutical composition formed by a solution of 〇mpa.s -1 or less. (53) The pharmaceutical composition according to any one of the above (49), wherein the solution contains about 25% (w/v) or less of a polyol and a cosolvent polyol, and the pH is about 4 to about A pharmaceutical composition formed by the solution of 7. (54) The pharmaceutical composition according to any one of the above (49) to (52), wherein the solution contains about 10% (w/v) to about 25% (w/v) of a monohydric alcohol and about 40% (w) /v) to about 55% (w/v) of the cosolvent polyol' and the pH is a pharmaceutical composition formed from a solution of from about 4 to about 7. (55) A pharmaceutical composition comprising a pharmaceutical composition according to any one of the above items M9) to (52), wherein the pH is from about 5 to about 7. (The best mode for carrying out the invention) The pharmaceutical preparation solution of the present invention is filled in a container having a capacity of about 1 m L or more and a volume of about 20 mL or less, and the solution contains a concentration of about 1 mg/mL or more, and about 1 Omg/mL or less is an active ingredient selected from the group consisting of the arginine amide represented by the above general formula (I), a salt thereof, and a mixture of such hydrates, and contains at least a solution of water. In the general formula (I), 'R1' represents (2R,4R)-4-alkyl-2-carboxypiperidinyl. The alkyl group herein means a lower alkyl group such as a methyl group, an ethyl group, a propyl-16-(11) 1327910 group, an isopropyl group or a butyl group to a C5 group. R2 represents a phenyl group or a condensed polycyclic compound residue as defined below. The condensed polycyclic compound residue is a condensed polycyclic compound residue containing a benzene ring bonded to a sulfur atom of the above sulfonyl group in the general formula (I), and the condensed heterocyclic ring on the benzene ring is also The other ring may have a total number of carbon atoms of from 7 to 14 in the ring constituting the residue of the polycyclic compound.

The residue of the condensed polycyclic compound is preferably a bicyclic compound residue or a tricyclic compound residue. The bicyclic compound residue is preferably a 5-membered ring or a 6-membered ring group condensed on the benzene ring, and the 5-membered ring or the 6-membered ring group may also be a heterocyclic ring. The tricyclic compound residue is preferably a 5-membered ring or a 6-membered ring group condensed on a 5-membered ring or a 6-membered ring. The 5-membered ring or 6-membered ring group may also be a heterocyclic ring. The hetero atom of the above heterocyclic ring is formed, for example, an oxygen atom 'nitrogen atom, or a sulfur atom.

R2 may be substituted with one or more groups selected from the group consisting of lower alkyl groups, lower alkoxy groups or amine groups substituted with lower alkyl groups. As a low court base: for example, a lower alkyl group such as methyl, ethyl 'propyl, isopropyl, butyl 'isobutyl or tert-butyl C1 to C5, and f as a lower alkoxy group, such as a a lower alkyl group of C1 to C5 of an oxy group, an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group, and an amine group substituted with a lower alkyl group, for example, substituted by the above lower alkyl group An alkylamino group or a dialkylamino group. Specific examples of the condensed polycyclic compound residue represented by R2 include an Anthryl group, a phenathry fluorenyl group, a benzofuranyl group, a dibenzothienyl 'phenoxathiinyl group, a quinolyl group, a carbazolyl group. (哩哩基), acridinyl (Dy -17-(12) 1327910 yl)' phenazinyl (phenazinyl), phenothiaziny (phenothiazine), phenoxazinyl (phenothrazinyl), benzoxanthyl , f]uoreny](fluorenyl)' 2,3-dioxabenzopyranyl, thioxantheneyl (thioxyl), naphthyl, tetrahydronaphthyl, isotinoyl, tetrahydro morpholinyl, and Hydrogen isoquinolyl and the like. In the above general formula (I), the benzene ring of the polycyclic compound residue is bonded to the sulfur atom of the sulfonyl group in the general formula (I), but the bonding position on the benzene ring is not particularly limited.

Specific compounds contained in the arginine amide are, for example, the following compounds. (2R,4R)-l-[N2-(3-isopropoxybenzenesulfonyl)-L-spermine fluorenyl]-4-methyl-2-piperidinecarboxylic acid; (211,411)-卜[>^-(3,5-Dimethyl-4-propoxybenzenesulfonyl)-[-arginylfluorenyl]-4-methyl-2-piperidinecarboxylic acid; (2R, 4R )-l-[N2-(5,6:7,8-tetrahydro-2-naphthalenesulfonyl)-L-spermine fluorenyl]-4-methyl-2-hydrazine residual acid,

(2R,4R)-l-[N2-(5-dimethylamino-b-naphthalenesulfonyl)-L-spermine-indenyl]-4-methyl-2-piperidinecarboxylic acid; (211,411 )-]-[&-(3-methyl-1:2,3,4-tetrahydro-8-porphyrinsulfonyl)-L-spermineinyl]-4-methyl-2-piperidin (2R,4R)-Bu [N2-(2-dibenzothiophenesulfonyl)-L-spermine oxime]·4_methyl-2-piperidinecarboxylic acid; (2R,4R) -〖-[N2-(2:4-dimethoxy-3-butoxybenzenesulfonyl)-L-spermine fluorenyl]-4-methyl-2-piperidinecarboxylic acid; (2R, 4R)-]-[N2-(3:5-dimethyl-4-propoxybenzenesulfonyl)-L-fine-18- (13) (13)1327910 Amidino]-4-ethyl -2 - piperidine carboxylic acid; (2R: 4R)-l-[N2-(3-ethyl-), 2,3S4-tetrahydro- 8-D quinolinylsulfonyl)-L-spermine fluorenyl ]-4-methyl-2·piperidinecarboxylic acid; (2R,4R)-l-[N2-(2 - yesterday Q 醯 醯)-L-spermine fluorenyl]-4-methyl-2 - piperidine carboxylic acid; (211,411)-1-[1^2-(2-oxasulfonyl)-1-arginylamine]-4-methyl-2-piperidinecarboxylic acid; (2R ;4R)-l-[N2-(2-phenothiasulfonyl)-L-spermine oxime]-4-methyl-2-piperidinecarboxylic acid; (2R,4R)-l-[N2 -(2-oxasulfonyl)-L-spermine oxime]·4·methyl-2-piperidinecarboxylic acid; and (2R,4R)-l-[N2-(7-methyl-2- Naphthalene Acyl) -L- spermine acyl] -4-methyl-2-piperidine carboxylic acid. The above-mentioned "most suitable" may be, for example, the above-mentioned ar § atroban. The above arginine amides may be an isomer of an optical isomer or a diastereomer, and any of these may be arginine amide or any isomer may be used. mixture. The above-described arginine amides can be easily produced by the method described in JP-A-56-33499, JP-A-H05-33499, and the like. Further, the arginine amide of the present invention can form an addition salt with various inorganic or organic acids or inorganic or organic bases according to the method described in JP-A-56-52267 or the like. . The pharmaceutical preparation of the present invention is preferably used as an injection, and when used as a 19-(14) (14) 1327910 injection, it can be diluted and used at the time of use. Further, the pharmaceutical preparation of the present invention can also be used, and a drip agent is prepared at the time of use. For example, a pharmaceutical preparation of the present invention can be added to an infusion to prepare a drip. Or it can be added to the dialysate for use during dialysis. The container to be used in the pharmaceutical preparation of the present invention is not particularly limited as long as it has a capacity of about 1 mL or more and a container of about 20 μL or less. A glass needle tube, a glass or plastic tube bottle, a polymer bag, or the like which is usually used for filling a pharmaceutical preparation can be suitably used. When considering the convenience of the medical site, the container capacity is preferably about 1 mL or less, preferably about 2 mL. The pharmaceutical preparation of the present invention contains the arginine amide represented by the above general formula (I) having a concentration of about 1 mg/mL or more and about i〇mg/mL or less as an active ingredient, and the concentration is about 5 mg/mL. should. The weight of the arginine amide contained in the container is preferably about mg0 mg. The container is preferably a glass needle tube. When the pharmaceutical preparation of the present invention considers, for example, a pharmaceutical preparation filled with a needle-type tube type, and after sucking the solution to the syringe, mixing the solution in the infusion to prepare a drip agent, it is required to contain a solution which is easily attracted to the syringe. . As such a pharmaceutical preparation, the viscosity of the solution is 2 5 t, at a shear rate of about 3 5.8 s -1 , preferably about 15 mPa · s -1 or less, and the viscosity of the solution is at 25 ° C 'about 7〗. At a shear rate of 6S-1, it is preferably about l〇mpa.s-]. The viscosity can be as shown in the examples below, at 25. (The following is measured using a rotary viscometer (Type B). The solution contained in the pharmaceutical preparation of the present invention, although containing at least water, does not exclude the presence of other solvents. The above solution contains 3〇% -20- (15) (15) 1327910 (w/v) or more of water is preferred. It is especially preferred to use a solution containing 35% to 55% (w/v) water. The dissolved concentration is about 1 mg/mL or more, and about l〇mS. The composition of the arginine amide solution of /mL or less is not particularly limited, and may be various compositions. As an example of a suitable formulation, for example, a formulation in which a monohydric alcohol for arginine can be added is used. Monohydric alcohol, as long as any pharmaceutically acceptable ones such as methanol, ethanol, etc., can be used. However, in the present invention, it is preferred to use ethanol. When using ethanol, it is considered that the inhibition center of ethanol is used in two, in solution The concentration is about 25% (w/v) or less, preferably 20% (w/v) or less, especially 10% to 25% (w/v), and 10% to 20% (w/v). Good, 15% to 20% (w/v) is the best. When considering the safety and reducing the amount of monohydric alcohol, a polyol can be added as a cosolvent. In this specification, a polyol is used. It refers to an alcohol of 2 or more yuan, but does not contain the saccharide. As a polyol, it can be used as long as it is pharmaceutically acceptable. However, in the present invention, a 2 or 3 membered polyol is preferred, and glycerin is preferred. The content of the polyol is not particularly limited, and may be used from about 3 % (w/v) to about 60% (w/v), from about 40% (w/v) to about 55% (W / V). In the pharmaceutical preparation or the pharmaceutical composition of the present invention, a saccharide may be used, but as the saccharide, for example, a saccharide such as glucose or fructose, or a sugar alcohol such as xylitol or sorbitol temple may be mentioned. It is preferred to use sorbitol. Of course, the viscosity of the solution is increased by using a saccharide, and it is not preferable to add a large amount of saccharides in general. Therefore, the pharmaceutical preparation of the present invention preferably contains a large amount of saccharides, for example, a saccharide content of about 30% (W). /V) is preferably 25% or less (w/v) or less. 21 - (16) 1327910 Further, it is preferable that the drug is not substantially contained. The pharmaceutical preparation of the present invention is based on dissolving arginine amide. It can be prepared by containing a solution of the above monohydric alcohol or the like. In the solution, a polyol can be added as needed. / or sugars. There are no special restrictions on the order, conditions, etc. when dissolved, but the first arginine amide is dissolved in monohydric alcohols, or monohydric alcohols. Mixtures with polyols and/or sugars, and then It is advisable to add water.

The pharmaceutical preparation of the present invention is an ampoule preparation which can substantially inhibit the formation of a substance other than the effective ingredient after heat sterilization. However, when stored at 40 ° C for 6 months after heat sterilization, it is preferred that the amount of the substance other than the active ingredient (decomposed product) is suppressed to about 0.2% or less. Whether or not the pharmaceutical preparation which is formed to substantially inhibit the production of the active ingredient is as described in the following examples. The solution after heat sterilization can be easily confirmed by HP LC analysis. The heat sterilization system here is not particularly limited as long as it can be secured as a medicine. However, it is usually used at 1 2 1 ° C for 20 minutes for heat sterilization and the same degree of effect. The substance (decomposed product) other than the active ingredient of the present invention may, for example, be a decomposition product derived from an active ingredient or other unknown compound. For example, when the active ingredient is a r g a t r 〇 b a η, the substance other than the active ingredient contains the following main decomposition product (decomposed product i) and other unknown compounds. —2 2 - (17) 1327910

As a pharmaceutical preparation which can substantially inhibit the production of a substance other than the active ingredient after heat sterilization, for example, a pharmaceutical preparation containing the above-mentioned solution containing arginine-branched amine and then adjusting the pH of the solution before heat sterilization can be prepared. The pH of the solution is preferably from about 4 to about 7, more preferably from about 5 to about 7. The pH adjustment can be carried out using a conventional pH adjuster. For example, a P Η adjusting agent such as hydrochloric acid or sodium hydroxide can be used. As described above, the preparation of the arginine-containing amide amine solution is carried out by adjusting the pH, etc., and then dispensing into a container such as a cleaned needle tube, which is fused and sealed, and then sterilized according to the heat sterilization. Pharmaceutical preparations. The pharmaceutical composition provided by the present invention comprises the above-mentioned arginine amide represented by the above general formula (I), which contains a concentration of about 1 mg/mL or more and about 1 〇mg/mL or less as an active ingredient. And a salt, and a substance in which the hydrates are grouped, and a viscosity of about 35.8 s_1 at a shear rate of about 5,5 s. This pharmaceutical composition is filled with a container having a capacity of about 1 mg/mL or more and about 20 mg/mL or less. However, the capacity of the container is not limited to the above. (18) (18) 1327910 [Embodiment] The present invention will be more specifically described below based on examples, but the scope of the present invention is not limited to the following examples. The argatroban used in the following examples is manufactured according to the method described in JP-A No. 0_649. Further, any of the following viscosity values were measured under the following conditions. Measuring machine: Type B viscometer (manufacturer: Tokimec Co., Ltd., vendor: Toki Industries Co., Ltd.)

Measurement temperature: 2 5 °C Rotation times: 60 rpm (according to the operating instructions, at 10 mPa. s- 1 or more, measured at 30 rpm, shear rate is 71.58 s at 60 rpm and 3 5.7 9 s- 1 at 30 rpm) Example 1 As shown in Table 1 and 1, 10 g of ethanol (99.5%), 20.0 g of sorbitol, 30.0 g of glycerin and 500 g of argatroban were weighed in a 100 ml measuring flask. Add water for injection and become I00ml$. Soak the stomach bottle to 25. (: the sink, the solution obtained by ultrasonic irradiation to obtain a clear solution. 2 to 4 shown in Table 1, the same as the concentration shown in the table _ take the ingredients of ethanol, sorbitol and concentrated glycerin, A pharmaceutical composition containing argatroban of 5 mg/ml was added to the water for injection. As a result, the pharmaceutical composition of any of the compositions of 1 to 4 was obtained at room temperature of 25 ° C, and was colorless and transparent. 24 (19) (19) 1327910 Similarly, regarding the formulations shown in Tables 2 and 3, a pharmaceutical composition containing 5 mg/ml of argatr〇ban was prepared in the same manner (in Tables 2 and 3, the argatroban concentration system) The concentration of ethanol and concentrated glycerin is expressed in % (w/v) in mg/ml. In addition, the viscosity of each preparation and the stability of storage at 4 ° C for 24 hours are shown in Tables 2 and 3. A pharmaceutical composition containing argatroban having a concentration of about 5 mg/ml can be obtained. These pharmaceutical compositions have a viscosity which is easily attracted to the syringe, and have good stability. Similarly, the formulations shown in Table 4 are similarly prepared. 5mg/ml of argatroban's pharmaceutical composition (in Table 4, argatroban concentration is in mg /ml indicates that the concentration of ethanol and concentrated glycerin is expressed as % (w/v). In addition, the viscosity of each preparation is shown in Table 4. A medicine containing argatr 〇ba η having a concentration of about > mg / m 1 can be obtained. Compositions, such pharmaceutical compositions have a viscosity that is easily attracted to the syringe. Table] Pharmaceutical Composition 1 2 3 4 Argatroban 5 mg/m 1 5 5 5 B. Alcohol 1 0 w / v % 40 10 1 5 Yamanashi Sugar alcohol 2 0 w / v % 30 Concentrated glycerol 3 0 w/v% 55 45 Dissolved at room temperature, dissolved, dissolved, dissolved, dissolved at 4 °C, good stability, good, good, good (20) 1327910, Table 2, pharmaceutical composition, 5 6 7 8 Ar gatroban 5 5 5 5 Ethanol 10 1 5 20 25 Concentrated glycerol 50 50 50 50 Dissolved at room temperature, dissolved, dissolved, dissolved, dissolved at 4 °C, good stability, good good viscosity (25 ° C) 6.0 7.1 7.9 9.0 Table 3 Pharmaceutical composition 9 10 11 12 13 14 Argatroban 5 5 5 5 5 5 Ethanol 20 25 3 0 15 20 3 0 Concentrated glycerol 45 45 45 40 40 40 Dissolved at room temperature, dissolved, dissolved, dissolved, dissolved, dissolved at 4 °C Good stability, good, good, good, good, good Degree (25t) 6.7 7.4 7.9 5.0 5.6 6.6 Table 4 Pharmaceutical composition 14-1 14-2 14-3 Argatroban 5 5 5 Ethanol 12 14 17 Concentrated glycerol 50 45 40 Viscosity (2 5 ° C) 6.5 6.3 5.5 Example 2 -26- (21) 1327910 Weigh about 200 mg of argatroban in a triangular conical flask, and add 1 〇ml of the previously prepared solution of the composition shown below. Thereafter, the mixture was immediately stirred in a thermostat at 2 ° C using a stirrer. After 24 hours, a suspension of 1 ml was taken and filtered through a membrane filter of 0.45 μηιηι to obtain a sample for HPLC.

Reset the temperature of the thermostat to 2 5 °C and continue stirring. After 24 hours, 1 ml of the suspension was taken and passed through a membrane filter of 0·45 μm to obtain a sample for P L C. The results of measuring the viscosity and the solubility at 2 ° C and 2 5 r for each solution are shown in Table 5 below (the solubility in the table is expressed in mg/m), and the formulation concentration is expressed in w/v%. ). The resulting pharmaceutical composition has a viscosity that is easily attracted to the syringe. Further, it is understood that the solubility of argatroban increases when the amount of ethanol is increased. Table 5 Pharmaceutical composition 15 16 17 18 19 Lysate composition (w/V %) Ethanol 8% 10% 8% 10% 6.5% Glycerol 5 0% 5 0% 2 9.5% 2 9.5% 2 9.5% Sorbitol 2 0% 2 0% 3 0% Viscosity (25°c, CP) 5.48 5.8 1 6.10 6.65 9.40 Solubility (mg / m L) 2 °C 5.2 1 6.7 1 3.46 4.99 2.67 2 5 °C 6.22 8.12 3.86 5.42 3.93 Implementation Example 3 The same procedure as in Example 2 was carried out to "modulate the solution of the following composition" to measure the viscosity of -27-(22) (22) 1327910. The results are shown in Table 6 (the solubility in the table is expressed in mg/ml, and the formulation concentration is expressed in w/v%). Table 6 Pharmaceutical Composition 20 2 1 22 Ethanol 0 0 0 Glycerol 45 55 45 Sorbitol 15 Solubility (2 ° C) 1.47 1.90 1.50 Viscosity (25 ° C) mPa · s 3.54 5.00 6.75 Example 4 Same as Example 1 The medicinal composition of the formulation shown in Table 7 below (the ethanol and glycerol concentrations in the table are expressed in % (w/v)) was measured to determine the concentration of sorbitol added to the concentration of 40% (% by weight). Viscosity of each composition. The concentration of argatroban is 5 mg/ml. The result is shown in Figure 1. The results shown in Figure 1 show that the viscosity of the solution is greatly affected by the concentration of sorbitol. Table 7 Pharmaceutical composition 23 24 25 26 27 Ethanol 5 5 5 7 10 Glycerol 20 30 3 5 3 5 30 Example 5 Put 450 kg of glycerin in a 1 L beaker, stir in advance, add 1 50 g -28- (23) (23) 1327910 Ethanol, mixed with stirring. 5 g of argatroban was added to the mixture, and dissolved by heating as needed. 380 g of distilled water for injection was added to the solution and mixed under stirring. 0.0 2 4 m ο 1 / L of hydrochloric acid was added to the resulting solution to adjust the pH to about 6, and distilled water for injection was added to make the total amount 1 L. This solution was heat-sterilized (1 2 1 °C, 20 minutes), and the results of HLPC investigation of substances other than the active ingredient were as shown in Fig. 2. As is apparent from Fig. 2, the pharmaceutical composition of the present invention substantially inhibits the formation of substances other than argatroban even after heating and quenching. The measurement of HLPC was carried out under the following conditions. Modulation of the sample: 2 ml of the sample was accurately weighed, and the mobile phase (A) was added, and correctly 20 mL' was used as the sample solution. Test conditions: Detector: UV spectrophotometer (measurement wavelength: 254 nm) Column Nucleosil ODS 5 // m > 4.61. D . x 2 5 0 cm (C h em co) Column temperature: 4 5 t Phase: 0.25% acetic acid buffer solution (pH 5): methanol = 55:45' v / v (0 25% acetic acid buffer solution: adding water to 25 mL of acetic acid into ] 000 mL 'methanol solution to pH 5)

Flow rate: 1 mL/min Injection volume: 1 〇μ L HPLC machine: pump for LC — ]0AD, injection unit for one 29- (24) (24) 1327910 SIL — ]0A, thermostat for CTO — 10A, The detector was SPD - 0A (any one was Shimadzu Corporation). Example 6 450 kg of glycerin was placed in a 1 L beaker, stirred in advance, 150 g of ethanol was added, and the mixture was stirred with stirring. 5 g of argatroban was added to the mixture and dissolved by heating as needed. 380 g of distilled water for injection was added to the solution and mixed under stirring. Add 〇.〇24mol/L hydrochloric acid or 0.02 5m〇I/L sodium hydroxide to the obtained solution, adjust the pH to about 4, 4.5, 5, 5.5, 6, 6.7' or 7.5' to the injection steaming hall. Water so that the total amount is 1 L. The resulting solution was heat-sterilized (1 2 1 ° C; 20 minutes), and the formation of a substance other than the active ingredient was investigated by HLPC (the same conditions as in Example 5). The result is shown in Figure 3. From the results of Fig. 3, it is understood that pH 4 to pH 7 is preferably pH 5 to pH 7 to suppress the formation of substances other than the active ingredient. Example 7 Approximately 25 mg or 100 mg of argatroban' was added to a covered triangular conical flask. 5 ml of the previously prepared solution having the composition shown in Table 8 was added thereto. The pH of each solution was adjusted using hydrochloric acid or sodium hydroxide. Immediately thereafter, the mixture was stirred using a stirrer in a constant temperature library at 5 °C. After 24 hours, a suspension of 1 m was taken and filtered through a membrane filter of 0.4 5 μm to obtain a sample for HPLC. The solubility of each solution is as shown in Table 8. 0 -30- (25) (25) 1327910 U_____1 Dissolved solution \\ E-4 E-5 E-6 E-7 E-8 E-9 γΛι ____-- -- 7. Alcohol] 5% 15% 1 5% 2 0% 2 0% 2 0% ------ Concentrated glycerin 4 0% 45% 5 0% 4 0% 45% 5 0% Appropriate amount of water Appropriate amount of appropriate amount ^_---- pH of the solution '1 5.98 6.00 5.99 5.92 6.0 1 5.99 5. (: Solubility C mg / m L) 5.10 6.52 8.53 >5 >5 >5 As mentioned above, it is confirmed that it contains 15% and 20% ethanol (99.5), and contains 40, 45 and 50% thick. Any of the glycerol solutions dissolves argatroban of 5 mg/mL or more. Example 8 In a needle tube (20 ml), hydrochloric acid or sodium hydroxide was added to a formulation containing lOnig argatroban, 300 mg of ethanol (99.5), and 900 mg of concentrated glycerin, followed by adding water for injection to 2 ml to prepare PH5. .0 to 6.8 injections "heat sterilization (121 ° C, 20 minutes) after these injections, stored at 4 ° ° C / 75% RH for 6 months, review about various pH injections in argatroban Stability. The production of substances other than the active ingredient was measured by the following method. The results of the review are shown in Table 9. 31- (26) (26) 1327910 Measurement method Take 4 m 1 of this product, and add the mobile phase to 10 m 1 as a sample solution. 5 ml of this solution was accurately weighed, and the mobile phase was added correctly to become 50 ml. 5 ml of this solution was accurately weighed, and the mobile phase was added correctly to become 100 m 1 ' as a standard solution. For the 50 μL sample solution and the standard solution, the test was carried out in accordance with liquid chromatography under the following conditions. The peak area of each liquid was measured by an automatic integration method, and the ratio of the respective peak areas of the sample solution was determined with respect to the peak area of argatr 〇b an of 200 times the standard solution. Test condition detector: UV spectrophotometer (measurement wavelength: 2 5 9 nm) Column: octadecyl decane for liquid chromatography with 5 μηι in a stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm Silicone gum. Column temperature: a certain temperature around 4 5 t Mobile phase: dilute acetic acid (100) (1 - 400), add ammonia test solution to adjust the pH to 5.0. 450 ml of methanol was added to 550 ml of this solution. Flow rate: adjusted so that the residence time of the first eluted peak of the two peaks of argatroban was about 50 minutes. Area measurement range: A range of about 1.4 times the residence time of the first eluted peak of the two peaks of a r g a t r 〇 b a η after the peak of the solvent. (27) 1327910 Table 9 Number of retention times of similar substances pH 5.0 of the injection solution 5.5 6.4 6.6 6.8 9.5 minutes around 1~3 <0.05* <0.05* <0.05* <0.05* <0.05* <0.05 * Near 10 minutes 1~3 <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* Initial decomposition product i 1 0.07 0.06 0.06 0.05 0.05 0.05 (12 points) 2 0.07 0.06 0.06 0.06 0.05 0.05 3 0.07 0.06 0.06 0.05 0.05 0.05 36~48 points 1~3 <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* Each 9.5 points nearby 1 Similar 2 <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* The amount of substance 3 is near 10 points 1 (%) 6 2 <0.05* <0.05* <0.05* <;0.05*<0.05*<0.05* 3 month decomposition product i 1 0.14 0.12 0.11 0.10 0.10 0.10 (12 points) 2 0.14 0.11 0.10 0.10 0.10 0.10 3 0.14 0.11 0.11 0.10 0.10 0.10 36~48 minutes 1 0.07 0.05 0.06 2 0.07 <0.05* <0.05* <0.05* 0.05 0.05 3 0.08 0.05 0.05 *: All 3 times were 0.05% underfill.

:-33- (28) (28) 1327910 In the range of pH 5.0 to 6_8, the decomposition product I is 0.10 to 0.14%, and other similar substances (other unknown substances) are 0. 10% not full, confirming the present invention The argatroban needle tube formulation is stable in this pH range. Example 9 450 g of glycerin was placed in a 1 L beaker and stirred in advance, and 150 g of ethanol was added thereto, followed by mixing under stirring. To this mixture, 5 g of argatroban' was added and dissolved as needed. 380 g of distilled water for injection was added to the solution and mixed under stirring. 〇.〇 24 mol/L of hydrochloric acid or 0.025 mol/L of sodium argon oxide was added to the resulting solution to adjust the pH to about 6 ′ to the distilled water for injection to make the total amount 1 l. Each 2 m 1 of this solution was dispensed into each of the needle tubes to obtain a needle preparation. The argatroban needle preparation at this time is as follows. Table 10

With the purpose of the ingredient name, the active ingredient argatroban 1 0 mg, the dissolving agent, anhydrous ethanol, 300 mg, the solubilizing agent, concentrated glycerol, 900 mg, pH adjusting agent, hydrochloric acid, pH adjusting agent, sodium hydroxide, appropriate amount of solvent, suitable amount of water for injection, 2 m L ( 29) (29) 1327910 The comparative example was measured in the same manner as in the above-mentioned Example 1, and it was measured in the following Table 1 as a pharmaceutical composition represented by "comparative composition", and the Japanese Patent Publication No. 3-77.2 The pharmaceutical composition described in Example 6 (the known composition of r shown in the table) and the commercially available preparation in the United States are sold under the trade name argatroban ("US commercial preparation" shown in the table: 40.混合g of ethanol, 3 〇. 〇g sorbitol, and 20.0g of mixed water for injection, 'force □ heat into 50 ° C, force into the 〇 〇 之 argatroban, dissolve it, add The viscosity of the preparation obtained by using water for injection to make 100 m I. The results are shown in Table 11. The viscosity of the commercially available formulation in the United States at 25 ° C is 13.8 mPa. s - 1 'This is commercially available in the United States at a rate of 30 r p m. Further, for the φ ά degree of 20 m P a . s or more, the B-type measurement viscosity is carried out at 15 r p m . In the table]1, the "operability of the syringe" is used to indicate the operability (the required force and the finger and palm) when the solution is used in the syringe. Load). When a 22G or 23G injection needle is used which is thinner than 21G, since the operability is further lowered, the viscosity of the pharmaceutical composition is 10 m P a · s _] or less, and it is preferable to have a low viscosity. As shown in Table 11, any of the known compositions and commercially available formulations in the United States were inferior in operability. In the case of a high-viscosity solution of 20 mPa·s or more, there is a possibility that an unsuitable condition (it is difficult to charge the correct capacity) occurs in the steps of dispensing the needle tube during manufacture. - -35- 1327910 (30) Table η Known composition comparison composition US commercial preparation argatroban 10% 5mg/ml 10% Ethanol 2 0% 5% 4 0% Glycerol 2 0% 3 5% Sorbitol 3 0 % 3 0% 3 0% Viscosity (25t:) 2 1.1 26.5 13.8 Difficulty in handling by syringe (21G)

(industrial use)

According to the present invention, there is provided a novel pharmaceutical preparation and pharmaceutical composition comprising, as an active ingredient, a substance selected from the group consisting of the above-mentioned arginine 'melamines, salts thereof, and hydrates thereof. The pharmaceutical preparations and pharmaceutical compositions of the present invention have the advantages of high convenience and safety at the medical site, good storage stability, and easy and convenient manufacture. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the relationship between the concentration of sorbitol and the viscosity of Example 4. Figure 2 is a diagram showing the hplc record of Example 5. Fig. 3 is a graph showing the relationship between ρ Η of a pharmaceutical preparation of Example 6 and generation of a similar substance. —3 6 —

Claims (1)

1322210_ j public good book, application for patent scope, subscription correction page 93107492 patent application i Chinese patent application scope U Republic of China 1. A pharmaceutical composition 'characterized by containing argatroban below 10mg / mL, in solution w / v) monohydric alcohol and 40% to 55% (w/v) &ol, and no sugar containing solution. 2. A pharmaceutical composition' characterized by a argatroban solution containing from 1% to 254% to 5% (w/v) of a co-solvent. 3. If the patent application scope 1 or 2 is made from a solution of pH 4 to pH 7. 4. As claimed in the first paragraph of the patent, $2, which is formed from a solution of pH 5 to pH 5. 5. As claimed in claim 1 or 11 2 wherein the monohydric alcohol is ethanol. 6. For the scope of patent application, item 1 or 2, where the binary or trihydric alcohol is glycerol! Case E was amended on May 4, 1999, with 1 mg/mL or more and 10% to 25% (3) A pharmaceutical composition comprising a pharmaceutical composition of 5 mg/mL (w/v) of a monohydric alcohol and a trihydric alcohol, and having no sugar I, a pharmaceutical composition thereof, a pharmaceutical composition of the item Pharmaceutical composition,